PROJECT SUMMARY/ABSTRACT Abnormal calcium (Ca) and phosphorus (P) metabolism are central to the development of chronic kidney disease-mineral bone disorder (CKD-MBD), which causes cardiovascular and bone disease leading to cardiovascular events, bone fractures, and increased risk of death. The various dietary and pharmaceutical treatments for CKD-MBD affect both Ca and P metabolism, yet major knowledge gaps exist on how these treatments affect whole-body physiology of both ions. The lack of understanding on Ca and P metabolism in CKD-MBD progression precludes the development of effective therapies. The goal of this project is to produce preliminary data on the effects of the commonly prescribed dietary phosphorus restriction on whole-body Ca and P balance and kinetics in patients with CKD, to support a larger future clinical study. The specific aims are to determine 1) intestinal Ca and P fractional absorption and 2) Ca and P balance and full kinetics, effect sizes and variance estimates in patients with CKD on a low Ca diet with high P diet versus dietary P restriction. In a randomized cross-over design, four adult patients with moderate-stage CKD will be studied on a controlled diet of either low dietary Ca intake and high dietary P intake, representative of a typical American diet, or a low dietary Ca intake with a dietary P restriction as commonly prescribed. After screening to determine eligibility, enrolled patients will be given the randomly assigned controlled diet for 1 week as outpatients, and then admitted to the clinical research center for a 48-hour absorption testing protocol that will utilize oral and intravenous doses of stable Ca-44 and radioactive P-33 isotopes. Serial blood draws will be taken over the 48-hour inpatient period, along with timed urine and complete fecal collections. Fractional Ca and P intestinal absorption will be determined by kinetic modeling of serum and urine measurements of the isotopes after oral and intravenous dosing. Two patients will be studied for an additional 12-days as inpatient continuing on the controlled research diet with blood draws and timed, complete urine and fecal collections to determine whole-body Ca and P balance over 2-weeks, as well as full Ca and P kinetics obtained by modeling the serum, urine, and fecal isotopic data, which will give rates of Ca and P transfer to and from various body pools (e.g. to and from bone). Following a 1- week washout, patients will crossover to be studied on the other dietary condition. It is expected that this study will produce the necessary effect size and variance estimates on the effect of dietary P restriction on Ca and P absorption, balance, and kinetics to adequately power a future clinical study. The long-term goal of this research is to determine effects of a variety of current and novel dietary and pharmaceutical interventions on whole-body Ca and P physiology with the goal of improving treatments for CKD-MBD. This relates to the mission of the NIDDK to support research aimed at improving the health and quality of life of patients with kidney disease.